University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

RNA Therapeutics Institute; Department of Biochemistry and Molecular Pharmacology; Department of Neurology; Graduate School of Biomedical Sciences

Publication Date

2020-08-31

Document Type

Article Preprint

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry | Molecular Biology | Nervous System Diseases | Structural Biology

Abstract

Toxic dipeptide repeat (DPR) proteins are produced from expanded G4C2 hexanucleotide repeats in the C9ORF72 gene, which cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥ 20 repeats inhibit the ribosome’s peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryo-EM structures reveal that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center. Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with the DPR proteins and restores peptidyl-transferase activity. Our results demonstrate that strong and specific binding of poly-PR and poly-GR in the ribosomal tunnel blocks translation, revealing the structural basis of their toxicity in C9ORF72-ALS/FTD.

Keywords

Biochemistry, ribosomes, Toxic dipeptide repeat (DPR) proteins, C9ORF72 gene, C9ORF72 gene, amyotrophic lateral sclerosis, ALS, frontotemporal dementia, FTD

Rights and Permissions

The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

DOI of Published Version

10.1101/2020.08.30.274597

Source

bioRxiv 2020.08.30.274597; doi: https://doi.org/10.1101/2020.08.30.274597. Link to preprint on bioRxiv.

Comments

This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.

Journal/Book/Conference Title

bioRxiv

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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